5-aminoalkyl and 5-aminocarbonyl substituted indoles

ABSTRACT

The present invention relates to 5-aminoalkyl and 5-aminocarbonyl substituted indole derivatives having formula (1), wherein R 1  is-(CH 2 ) n-1 -CONR 10 R 11 , -(CH 2 ) n -CONR 10 R 11  or (a), wherein R 10  and R 11  independently are selected from substituents defined herein; n is 1 to 3 and q is 2 to 5; G is N, C, or CH; Ar is phenyl optionally substituted with one or more substituents, or Ar is heterocyclic; R 2 , R 3 , R 4 , R 5  and R 6  are independently selected from substituents defined herein; m is an integer from 2-6; W is O or S; U is N or CH; Z is —(CH 2 ) p -, p being 2 or 3, or Z is —CH═CH—or 1 ,2-phenylene, or Z is—COCH 2 - or —CSCH 2 -; V is O, S, CH 2 , or NR 9 ; X is N, C, or CH; Y is N, C, or CH; provided at least one of X and Y is N; or a pharmaceutically acceptable acid addition salt thereof. The novel 5-substituted indoles have high affinity for α 1 -adrenoceptors and are considered useful for the treatment of diseases or disorders responsive to α 1 -adrenoceptor antagonists. Further, as the compounds are selective α 1 -adrenoceptor ligands they may be particularly useflul as PET or SPECT ligands.

[0001] The present invention relates to novel 5-aminoalkyl and5-aminocarbonyl substituted indoles having high affinity forα₁-adrenoceptors. The compounds of the invention are considered usefulfor the treatment of diseases or disorders responsive to antagonism ofthe α₁-adrenoceptor. Further, as the compounds are selectiveα₁-adrenoceptor ligands they may be particularly useful as PET or SPECTligands.

BACKGROUND

[0002] U.S. Pat. No. 4.710.500 discloses 5-substituted indolederivatives having the general formula:

[0003] The compounds may be substituted in position 5 with a substituentselected from halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro,lower alkylthio, CF₃, lower alkylsulphonyl, amino, lower alkylamino andlower di-alkylamino. The compounds are claimed to be potent andlong-lasting dopamine antagonists, and accordingly useful for thetreatment of psychoses. The compounds are also claimed to be strong 5-HTantagonists indicating effects in the treatment of negative symptoms ofschizophrenia and depression and for the treatment of cardiovasculardiseases.

[0004] The use of sertindole having the formula

[0005] as an antipsychotic is specifically claimed in EP-A2-0 392 959.

[0006] This type of compounds has also been shown to be useful for thetreatment of a range of other disorders including anxiety (WO 92/00070),cognitive disorders (WO 92/15303), abuse (WO 92/15302) and hypertension(WO 92/15301).

[0007] WO 92/15301 discloses compounds having affinity for theα₁-adrenoceptor. However, the compounds disclosed therein are notselective for the α₁-adrenoceptor.

[0008] Interest in the development of α₁-adrenoceptor antagonists hasprimarily focused on therapeutics for the treatment of cardiovasculardiseases (Hieble et al., Exp. Opin. Invest. Drugs, 1997, 6, 3657).Prazosin is the prototype of an α₁-adrenoceptor antagonist which hasvery potent peripheral effects. Prazosin is considered to have poor CNSpenetration although it in some animal models have shown effectsindicating potency in the central nervous system. Until now, noα₁-adrenoceptor selective antagonists with good CNS penetration to thehuman brain have been available.

[0009] Evidence exists indicating that blockade of α₁-adrenoceptorneurotranstission could be beneficial i the treatment of schizophrenia.Most classical antipsychotics including clozapine b potently toa,-adrenoceptors labelled with [³H]prazosin or [³H]WB-4101. Some studiesseem to indicate a central role of the α₁-component for the atypicalprofile of clozapine. ( Baldessarini, et al., Br. J. Psychiatry, 1992,160, 12-16 and Prinssen, et al., Eur. J. PharmacoL, 1994, 262, 167-170).Further, repeated co-administration of prazosin and haloperidol wasfound to reduce the effect of haloperidol on the firing of dopamineneurons in nigrostriatal areas, suggesting that the combination would beeffective as antipsychotic treatment without producing extrapyramidalside effects (EPS) (Chiodo, et al., J Neurosci. 1985, 3, 2539-2544).

[0010] It has also been suggested that centrally acting α₁-adrenoceptorantagonists will have antimanic effects while corresponding agonistswould be beneficial for the treatment of depression (Lipinsky, et al.,Life Sciences, 1987, 40, 1947-1963).

[0011] Labelled compounds of the present invention are considered to bevaluable PET (positron emission tomography) ligands and SPECT (singlephoton emission computed tomography) ligands due to their selectivityfor α₁-adrenoceptors.

[0012] Finally, it is well established that α₁-adrenoceptor antagonistsacting peripherally are useful for the treatment of benign prostatichyperplacia, hypertension and cardiac arrhyttnias and for the reductionof intra ocular pressure.

THE INVENTION

[0013] Accordingly, the present invention relates to 5-aminoalkyl and5-aminocarbonyl substituted indole derivatives having the generalformula:

[0014] wherein

[0015] R¹ is —(CH₂)_(n-1),—CONR¹⁰R¹¹, —(CH₂)_(n)-NR¹⁰R¹¹ or

[0016] wherein R¹⁰ and R¹¹ independently are selected from hydrogen,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl-C₁₋₆-alkyl, aryl, acyl,amino-C₁₋₆-alkyl and mono- or di-C₁₋₆-alkylamino-C₁₋₆-alkyl, R¹² ishydrogen or C₁₋₆-alkyl, n is 1 to 3 and q is2to5;

[0017] G is N, C, or CH; the dotted line meaning a bond when G is C, andthe dotted line meaning no bond when G is CH, or N;

[0018] Ar is phenyl optionally substituted with one or more substituentsindependently selected from halogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy,trifluoromethyl and cyano, or Ar is 2-thienyl, 3-thienyl, 2-furanyl,3-furanyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl,or 4-pyridyl;

[0019] R², R³, R⁴ and R⁵ are independently selected from hydrogen,C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy, halogen, trifluoromethyl, nitro,cyano, amino, C₁₋₆-alkylamino and C₁₋₆-dialkylamino;

[0020] R⁶ is hydrogen, or C₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl,C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkenyl, which may optionally besubstituted with one or two hydroxy groups, any hydroxy group presentbeing optionally esterified with an aliphatic carboxylic acid havingfrom two to twentyfour carbon atoms inclusive, or R⁶ is a group of theFormula II or III:

[0021] wherein m is an integer from 2-6;

[0022] W is O, or S;

[0023] U is N or CH;

[0024] Z is —(CH₂)_(p)-, p being 2 or 3, or Z is —CH═CH—or 1,2-phenyleneoptionally substituted with halogen or trifluoromethyl, or Z is —COCH₂-or —CSCH₂-; V is O, S, CH₂, or NR⁹, wherein R⁹ is hydrogen, orC₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkenyl which may optionally besubstituted with one or two hydroxy groups, or a C₃₋₈-cycloalkyl orC₃₋₈-cycloalkyl-C₁₋₆-alkyl group; X is N, C, or CH; Y is N, C, or CH;provided at least one of X and Y is N; and R⁷ is hydrogen, orC₁₋₆-alkyl; or a pharmaceutically acceptable acid addition salt thereof

[0025] In a particular embodiment, the present invention relates tocompounds wherein R¹ is —CONR^(10 R) ¹¹ or —(CH₂)_(n)-NR¹⁰R¹¹ whereinR¹⁰ and R¹¹ are independently selected from hydrogen, C₁₋₆alkyl andacyl.

[0026] In another particular embodiment, R⁶ is a group of formula II, inparticular a 2-imidazolidinon ring.

[0027] Such compounds include in particular the compounds:

[0028]1-(4-Fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidinyl]-N-methyl-1H-indole-5-carboxamide;

[0029]N,N-Dimethyl-1-(4fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidinyl]-1H-indole-5-carboxamide;

[0030]1-[2[4-[5-Dimethylaminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]2-imidazolidinon;

[0031]1-[2[4[5-Dimethylaminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-2-imidazolidinon;

[0032]1-[2[4-[1-(4fluorophenyl)-5-methylaminomethyl-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinon; or

[0033]1-[2[4-[5-aminomethyl-1-(4fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-irnidazolidinon;

[0034] or a pharmaceutically acceptable acid addition salt thereof.

[0035] The present invention also relates to a pharmaceuticalcomposition comprising at least one compound as above or apharmaceutically acceptable acid addition salt thereof and optionally asecond pharmaceutically active ingredient in combination with one ormore pharmaceutically acceptable carrier or diluents.

[0036] The present application relates to the use of a compound as aboveand optionally a second pharmaceutically active ingredient for thepreparation of a medicament for the treatment of a disorder or diseaseresponsive to antagonism of α₁-adrenoceptors.

[0037] The present invention also relates to a method for the treatmentof a disorder or disease responsive to antagonism of α₁-adrenoceptors ina mammal comprising administering a compound as above or an acidaddition salt thereof and optionally a second pharmaceutically activeingredient to said mammal.

[0038] In a particular embodiment, the second pharmaceutically activeingredient is an agent having antipsychotic activity.

[0039] In still another embodiment, the present invention relates to theuse of a compound as above or an acid addition salt thereof for thepreparation of a radio-labelled compound of the Formula I.

[0040] Diseases or disorders responsive to antagonism ofα₁-adrenoceptors includes psychosis, mania, benign prostatichyperplacia, hypertension, cardiac arrhytmias and reduction of intraocular pressure.

[0041] In a further embodiment, the present invention relates to acompound of formula I which is radio-labelled, e.g. with [¹¹C]-methyl.

[0042] Finally, the present invention relates to the use ofradio-labelled compounds of formula I in various biological assays,including binding assays, and in PET- or SPECT studies.

DETAILED DESCRIPTION OF THE INVENTION

[0043] When used herein halogen means fluoro, chloro, bromo or iodo.

[0044] The term C₁₋₆ alkyl refers to a branched or unbranched alkylgroup having from one to six carbon atoms inclusive, including groupssuch as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl and 2-methyl-1-propyl. Similarly, C₂₋₆-alkenyldesignates such groups having from two to six carbon atoms, containingone double bond, including groups such as ethenyl, propenyl and butenyland C₂₋₆ alkenyl designates groups having from two to six carbon atomsand containing one triple bond, including groups such as ethynyl,propynyl.

[0045] The term acyl refer to C₁₋₆-alkylcarbonyl, arylcarbonyl andaryl-C₁₋₆alkylcarbonyl.

[0046] The terms C₁₋₁-alkoxy, C₁₋₆-alkylaimino, C₁₋₆-dialkylamino,C₁₋₆-alkylcarbonyl, aryl-C₁₋₆ alkylcarbonyl etc. designate such groupsin which C₁₋₆-alkyl is as defined above.

[0047] The term C₃₋₈-g-cycloalkyl designates a monocyclic or bicycliccarbocycle having three to eight C-atoms including such groups ascyclopropyl, cyclopentyl, cyclohexyl, etc.

[0048] The acid addition salts of the compounds of the invention arepharmaceutically acceptable salts formed with non-toxic acids. Exemplaryof such organic salts are those with maleic, fumaric, benzoic, ascorbic,succinic, oxalic, bis-methylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, pahnitic, itaconic, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, and theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, and nitric acids.

[0049] The selectivity of the compounds of the invention for theα₁-adrenoceptor makes them particularly usefuil for the development oflabelled ligands useful in various biological assays and in PET andSPECT studies.

[0050] The compounds of the invention can be labelled by the use ofradio-labelled precursors, including ¹¹C-labelled precursors such as[¹¹C]methyl iodide, [¹¹C]methyl triflate, etc. The compounds may also belabelled with ¹⁸F or ¹²³I.

[0051] The compounds of the present invention can be prepared accordingto the procedures described below:

[0052] a) Reacting an indole derivative of the following formula

[0053] wherein R¹, R², R³, R⁴, R⁵ and Ar, are as defined above, with a4-piperidone of the formula

[0054] wherein R⁶ is as defined above A is an oxo group, or a—O—(CH₂)_(s)-O—chain, wherein s is 2, or 3;

[0055] b) reducing the tetrahydropyridine double bond in a compound ofthe formula

[0056] wherein R¹, R², R³, R⁴, R⁵, R⁶ and Ar, are as defined above;

[0057] c) reacting a compound of the formula

[0058] wherein R¹, R², R³, R⁴, R⁵, R⁶, G, and the dotted line, are asdefined above, with a compound of the formula

Ar-Hal

[0059] wherein Ar is as defined above and “Hal” is halogen, in thepresence of a metal catalyst,

[0060] d) reacting a compound of the formula

[0061] wherein R¹, R², R³, R⁴, R⁵, G, the dotted line and Ar, are asdefined above, with a reagent of formula R⁰-L wherein R⁰ isC₃₋₈-cycloalkyl, C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkyl, or C₂₋₆-alkenyland L is halogen, mesylate, or tosylate, or an epoxide of formula

[0062] wherein R is hydrogen, or C₁₋₄-alkyl;

[0063] e) reducing the carbonyl group of a compound of the formula

[0064] wherein R¹, R², R³, R⁴, R⁵, G, the dotted line and Ar, are asdefined above and R⁸ is C₃₋₈-cycloalkyl, C₁₋₅-alkyl,C₃₋₈-cycloalkyl-C₁₋₅-alkyl;

[0065] f) decarboxylating a compound of the formula

[0066] wherein R¹, R², R³, R⁴ and Ar, are as defined above, followed byreaction with a piperazine of the formula

[0067] wherein R⁶ is as defined above;

[0068] g) reacting a compound having the formula

[0069] wherein R¹, R², R³, R⁴, R⁵, G, the dotted line and Ar, are asdefined above with a compound having the formula Hal-R^(x) wherein R^(x)is a group of formula II or III as defined above and “Hal” is chloro,bromo, or iodo;

[0070] h) reducing a compound of the formula

[0071] wherein R², R³, R⁴, R⁵, R⁶, G, the doffed line, Ar and n are asdefined above;

[0072] i) reducing a compound of the formula

[0073] wherein R², R³, R⁴, R⁵, R⁶, R¹⁰, R¹¹, G, the dotted line, Ar andn are as defined above;

[0074] j) coupling a compound of formula

[0075] wherein R², R³, R⁴, R⁵, R⁶, G, the dotted line n and Ar are asdefined above with an amine of formula HNR¹⁰R¹¹ wherein R¹⁰ and R¹¹ areas defined above;

[0076] k) reacting a compound of formula

[0077] wherein R², R³, R⁴, R⁵, R⁶, G, the dotted line “Hal”, n and Arare as defined above with an amine of formula HNR¹⁰R¹¹ wherein R¹⁰ andR¹¹ are as defined above; or

[0078] l) reacting a compound of formula

[0079] wherein R², R³, R⁴, R⁵, R⁶, G, the dotted line, n and Ar are asdefined above with an amine of formula HNR¹⁰R¹¹ wherein R¹⁰ and R¹¹ areas defined above, using reductive conditions.

[0080] Methods for the preparation of the starting materials used in theabove processes are described in U.S. Pat. No. 4.710.500, WO 92/00070,PCT/DK99/00119 and in Perregaard et al., J.Med.Chem., 1992 (35),1092-1101, or can be prepared analogously to the procedures describedherein.

[0081] The 5-cyanomethyl-indoles may be prepared from the corresponding5-yano-indoles. The 5-cyano-indoles are hydrolysed to form thecorresponding carboxylic acid which are subsequently reduced to thecorresponding alcohols. Reaction with methanesulphonyl chloride to formthe corresponding 5-chloromethyl-indoles followed by reaction with acyanide afford the 5-cyanomethyl-indoles. Accordingly, homologouscompounds may be prepared in a sequential manner.

[0082] The carboxainides of formula XIV, carboxylic acid derivatives offormula XV, the alkylhalogenides of formula XVI and the aldehydes offormula XVII were prepared from the corresponding nitrites by methodsobvious to the chemist skilled in the art.

[0083] In method a) the reaction is performed under strong acidicconditions by heating. Trifluoroacetic acid or HCl in ethanol arepreferred as acidic catalysts.

[0084] In method b) and h) the reduction is preferably carried out atlow hydrogen pressures (3 Ato.) in the presence of platinum or palladiumon carbon black.

[0085] In method c) the arylation is preferably carried out at about160-210° C. in aprotic polar solvents as e.g. 1-methyl-2-pyrrolodinoneor hexamethylphosphoric triamide with K₂CO₃ as base and copper as acatalyst.

[0086] In method e) the reduction is preferably carried out with LiALH₄in 1THF or diethylether or with diborane in THF.

[0087] Method f) is a two step procedure in which compound X is firstdecarboxylated in the presence of an inorganic salt as e.g. LiCl orMgCl₂ in a polar solvent as e.g. diglyme, hexamethylphosphoric triamideor 1-methyl-2-pyrrolidone at elevated temperatures (120-150° C.).Finally, the appropriate piperazine is added and the temperature raisedto about 200° C. and kept there until the corresponding indoxyle hasdisappeared according to TCL analysis. The compounds of Formula X areconveniently prepared according to the procedures reported by P. C.Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1984).

[0088] The alkylations in method d), g) and k) are preferably performedas outlined in U.S. Pat. No. 4.710.500, WO 92/00070 and in Perregaard etal., J.Med.Chem., 1992 (35), 1092-1101

[0089] The amide in method i) is preferably reduced by means of standardconditions using Al₃, LiAlH₄ or borane in an aprotic solvent such asdiethyl ether or tetrahydrofiuran

[0090] The coupling reaction in step j) is preferably performed byformation of the active ester, the mixed anhydride, or the intermediateacid chloride and subsequent reaction with the amine. The reductiveamination reaction in method 1) is performed preferably by NaCNBH₄ in aprotic solvent such as methanol.

[0091] In the following, the invention is further illustrated by way ofexamples which, however, may not be construed as limiting.

Experimental Section

[0092] All reactions were carried out under a positive pressure ofnitrogen. Melting points were determined on a Büchi SMP-20 apparatus andare uncorrected. Mass spectra were obtained on a Quattro MS-MS systemfrom VG Biotech, Fisons Instruments. The MS-MS system was connected toan HP 1050 modular HPLC system. A volume of 20-50 μl of the sample (10μg/mL) dissolved in a mixture of 1% acetic acid in acetonitril/water 1:1was introduced via the autosampler at a flow of 30 μl/min into theElectrospray Source. Spectra were obtained at two standard sets ofoperating conditions. One set to obtain molecular weight information(MH+) (21 eV) and the other set to induce fragmentation patterns (70eV). The background was subtracted. The relative intensities of the ionsare obtained from the fragmentation pattern. When no intensity isindicated for the Molecular Ion (MH+), this ion was only present underthe first set of operating conditions. 1H NMR spectra were recorded ofall novel compounds at 250 MHz on a Bruker AC 250 or at 500 MHz on aBruker Avance DRX500 instrument. Deuterated chloroform (99.8%D) ordimethyl sulfoxide (99.9%D) were used as solvents. TMS was used asinternal reference standard. Chemical shift values are expressed inppm-values. The following abbreviations are used for multiplicity of NMRsignals: s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet,h=heptet, dd=double doublet, dt=double triplet, dq=double quartet,tt=triplet of triplets, m=multiplet. NMR signals corresponding to acidicprotons are generally omitted. Content of water in crystalline compoundswas determined by Karl Fischer titration. Standard workup proceduresrefer to extraction with the indicated organic solvent from properaqueous solutions, drying of combined organic extracts (anhydrous MgSO₄or Na₂SO₄), filtering and evaporation of the solvent in vacuo. Forcolumn chromatography, silica gel of type Kieselgel 60,230-400 mesh ASTMwas used.

EXAMPLE 1

[0093] 1-(4-Fluorophenyl)-1H-indole-5-carboxylic acid (1)5-Cyano-1-(4-fluorophenyl)-1H-indole (60 g) and potassium hydroxide (60g) was refluxed for 24 h in 90% ethanol. Water (1.5 L) was added and theaqueous phase extracted twice with isopropyl ether. After acidifyingwith hydrochloric acid, the title compound was filtered off and dried.Mp. 224-227° C. ¹H-NMR (DMSO):6.9 (d, IH), 7.45 (t, 2H), 7.55 (d, 1H),7.6-7.72 (m, 3H), 7.85 (d, 1H), 8.4 (s, 1H) 12.9-12.5 (1H, s, broad).

EXAMPLE 2

[0094] N,N-Dimethyl-1-(4fluorophenyl)-1H-indole-5-carboxamide (2)1-(4-Fluorophenyl)-1H-indole-5-carboxylic acid (20 g) and triethyl amine(8 g) in methylene chloride was cooled to −30° C. Ethyl chloroformate(8.7 g) was added and the temperature kept below −10° C. for 2 h.Dimethyl amine (16 g, 33% in ethanol) was added at −10° C. Afteraddition, the cooling bath was removed and the solution was stirred atroom temperature. Water and NaOH was added and the mixture was extractedwith methylene chloride after evaporation of the solvent the titlecompound was filtered through silica gel using ethylacetate/heptane20:80 and the solvent removed in vacuo. Yield: 12 g (oil). ¹H-NMR(CDCl₃) 3.10 (s, 6H), 6.70 (s, 1H), 7.20 (t, 2H), 7.20-7.35 (m, 2H) (m,3H), 7.80 (s, 1H)

EXAMPLE 3

[0095] 1-(4-Fluorophenyl)-N-methyl-1H-indole-5-carboxamide (3)1-(4-Fluorophenyl)-1H-indole-5-carboxylic acid (16 g) was dissolved inTHF (120 mL). 1,1′-Carbonyldiimidazole (15 g) was added and the solutionwas stirred at room temperature for 50 minutes. After cooling to 0° C.,methyl amine (125 mL, 2M in TBF) was added keeping the solution below10° C. After addition, the solution was stirred for 20 minutes at 0° C.and 45 minutes at room temperature. After removal of the solvent, thereaction mixture was dissolved in ethyl acetate, washed with water,saturated aqueous NaHCO₃ and dried over MgSO₄. The product wasrecrystalised from ethyl acetate/heptane 1:3. Yield: 12.3 g. Mp.126-128° C. Analysis: Calc: C: 71.63, H: 4.88, N: 10.44; Found C: 71.38,H: 5.05, N: 10.72 ¹H-NMR (DMSO): 2.80 (d, 3H), 6.80 (d, 1H), 7.45 (t,2H), 7.50 (d, 1H), 7.65 (m, 2H) (m, 2H), 8.20 (s, 1H), 8.40 (d, broad,1H)

EXAMPLE 4

[0096]1-(4-Fluorophenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole-5-carboxamide(4a)

[0097] A solution of 1-(4-Fluorophenyl)-N-methyl-1H-indole-5-carboxamide(3) (12.3 g) in a mixture of acetic acid (60 mL) and trifluoroaceticacid (15 rnL) was added during 0.5 h to a refluxing solution of4-piperidon, HCl, H₂O (36.6 g) in a mixture of acetic acid (50 mL) andtrifluoroacetic acid (100 mL). The reaction mixture was refluxed for 1h,cooled to room temperature and the solvents were removed in vacuo. Waterwas added and pH was adjusted to 10 by addition of aqueous NaOH. Theaqueous phase was extracted with ethyl acetate. The combined organicphases were washed with water and brine and dried over MgSO₄.Evaporation of the solvents in vacuo afforded the title compound as afoam.Yield 16 g . ¹H-NMR (DMSO) 2.48 (s, broad, 2H), 2.80 (d. 3H), 2.98(t, 2H), 3.50 (d, 2H), 6.40(s, 1H) 7.45 (t, 2H), 7.50 (d, 1H), 7.65 (dd,2H), 7.70-7.80 (m, 2H), 8.40 (s, 1H), 8.45 (q, broad, 1H)

[0098] The following compound was prepared accordingly:

[0099] N,N-Dimethyl-1(4-fluorophenyl)-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole-5-carboxamide (4b), oil, NMR (CDCl₃) 2.65 (m, 2H), 3.05 (s,6H), 3.25 (t, 2H), 3.70 (d. 2H), 5.00 (s, broad, 1H), 6.30 (s, broad,1H), 7.10-7.40 (m, 4H), 7.40-7.50 (m, 3H), 8.02 (s, 1H).

EXAMPLE 5

[0100]1-(4-Fluorophenyl)-N-methyl-3-(piperidin4-yl)-1H-indole-5-carboxamide(5a)1-(4Fluorophenyl)-N-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole-5-carboxamide(4a) (6.8 g) was dissolved in a mixture of acetic acid (150 mL) andtrifluoroacetic acid (25 mL). PtO₂ (300 mg) was added and the mixturewas hydrogenated at 3 ATO for 5 h at room temperature. The mixture wasfiltered and the solvent removed in vacuo. Water was added, pH adjustedto 10. The phases were seperated and the aqueous phase was extractedwith ethyl acetate. After removal of the solvent, the product wasfiltered through silica gel using ethylacetatelethanol/ TEA 50:50:5 asthe solvent. Evaporation of the solvents in vacuo afforded the titlecompound as a foam Yield 4 g. ¹H-NMR (DMSO)1.65 (2H), 1.95 (d, 2H), 2.70(t, 2H), 2.80 (d,3H)2.95 (t, 1H), 3.1 (d, 2H), 7.40 (t, 2H), 7.45-7,52(m, 2H), 7.65 (m, 2H), 7.75 (d, 1H), 8.25 (s, 1H), 8.45 (q, 1H)

[0101] The following compound was prepared analogously:

[0102]N,N-Dimethyl-1-(4-fluorophenyl)-3-(piperidin-4-yl)-1H-indole-5-carboxamide(5b), foam, ¹NMR (CDC₃) 1.75 (qd, 2H), 2.1 (d, 2H), 2.85 (dt, 2H), 3.00(tt, 1H) 3.15 (s, 6H), 3.25 (t, 2H), 7.10 (s, 1H), 7.15-7.35 (m, 31,7.35-7.50 (m, 3H), 7.80 (s, 1H)

EXAMPLE 6

[0103]5-Dimethylaminomethyl-1-(4fluorophenyl)-3-(piperidin-4-yl)-1H-indole(6a) LiAlH₄ (1.5 g) was slowly added to a solution ofN,N-dimethyl-1-(4-fluorophenyl)-3-(piperidin-4-yl)-1H-indole-5-carboxamide(5b) (4.25 g) in THF (50 mL) keeping the temperature below 40° C. Thesolution was stirred 3 h at 40 ° C. After cooling to 0° C., water wascareflilly added, the phases were separated and the aqueous phaseextracted with diethylether. The organic phase was dried over Mg₂SO₄ andthe solvent evaporated in vacuo. Yield: 3.5 g. (oil), ¹H-NMR (CDC₃) 1.70( 2H), 2.05 (d, 2H), 2.25 (s, 6H), 2.85 (td, 2H), 3.00 (tt, 1H), 3.20(d, 2H), 3.50 (s, 2H), 7.00 (s, 1H), 7.10-7.30 (m, 3H), 7.30-7.50 (m,3H), 7.60 (s, 1H).

[0104] The following compound was prepared analogously

[0105] 5-Dimethylaminomethyl-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydro-4-pyridyl)- 1H-indole (6b), oil,¹H-NMR: 2.30 (s, 6H), 2.50 (m, 2H), 3.20 (t, 2H), 3.50 (s, 2H), 3.70 (q,2H) 6.35 (m, 1H) 7.15- 7.35 (m, 4H), 7.40-7.55 (m, 3H), 7.85 (s, 1H)

EXAMPLE 7

[0106] 1-(4-Fluorophenyl)3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidinyl]-N-metiyl-1H-indole-5-carboxamide (7a)

[0107] 1-(4-Fluoropheny)-N-methyl-3-(piperidin4-yl)-1H-indole-5-carboxamide (5a)(4.4 g), K₂CO₃ (5.2 g), KI (1 g) and 1-(2-chloroethyl)-imidazolidin-2-on(2.2 g) was refluxed for 8 h in methyl isobutyl ketone. The solution wasfiltered hot and the residue washed with methyl isobutyl ketone. Afterevaporation of the solvents, the compound was dissolved in methylenechloride and washed twice with water. The compound was purified by flashchromatography (EtOAc/MeOH/TEA 80/15/5) Yield 3.5 g. Mp.: 150-155° C.(ethanolldiethyl ether 50/50). ¹H-NMR (DMSO) 1.75 (dq, 2H), 2.0 (d, 2H),2.15 (t, 2H), 2.45 (t, 2H), 2.82 (d, 3H), 2.85 (t, 1H), 3.02 (d, 2H),3.2 (q, 4H), 3.4 (q, 2H), 6.25 (s, 1H), 7.40 (t, 2H), 7.49 (m, 2H), 7.60(m, 2H), 7.70 (d, 1H), 8.20 (s, 1H), 8.4 (q, 1H)

[0108] The following compounds were prepared analogously:

[0109]N,N-Dimethyl-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]4-piperidinyl]-1H-indole-5-carboxamide(7b)

[0110] Mp. 172-176 (acetone). ¹H-NMR (CDCl₃) 1.80 (dq, 2H), 2.05 (d,2H), 2.15 (t, 2H), 2.55 (t, 2H), 2.90 (tt, 1H), 3.10 (m, 8H), 3.40 (m,4H), 3.50 (m, 2H), 4.80 (s, broad, 1H), 7.10 (s, 1H), 7.15-7.40 (m, 3H),7.35-7.50 (m, 3H), 7.80 (s, 1H). Analysis: Calc (corrected for ⅓ molacetone): C: 67.67, H: 6.91, N: 14.10, Found: C: 67.02, H: 6.92, N:13.82.

[0111]1-[2-[4-[5-Dimethylaminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinon (7c)

[0112] Mp 166-174° C. (acetone). ¹H-NMR (CDCl₃) 1.80 (q, 2H), 2.05 (d,2H), 2.18 (t, 2H), 2.25 (s, 6H), 2.57 (t, 2H), 2.85 (tt, 1H), 3.08 (d,2H), 3.40 (q, 4H), 3.45-3.55 m, 4H), 4.40 (s, 1H), 7.00 (s, 1H), 7.15(m, 3H), 7.30-7.50 (m, 3H), 7.60 (s, 1H).

[0113] 1-[2-[4-[5-Dimethylaminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1,2,3,6- tetrahydropyridin-1-yl]ethyl]-2-imidazolidinon(7d) Mp 146-148° C. (acetone). ¹H-NMR (CDCl₃) 2.30 (s, 6H), 2.60-2.75(m, 4H), 2.80 (d, 2H) 3.30 (d, 2H), 3.40 (q, 4H), 3.45-3.55 (m, 4H),4.70 (s, broad, 1H), 6.30 (s, broad, 1H), 7.10-7.25 (m, 4H), 7.30-7.50(m, 3H), 7.85 (s, 1H)

EXAMPLE 8

[0114]1-[2-[4-[1-(4-Fluorophenyl)-5-methylaminomethyl-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinon(8)

[0115] 1-(4-Fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]4-piperidinyl]-N-methyl-1H-indole-5-carboxamide(7a) (2g) and LiAIH4 was refluxed in dry THF (150 mL) for 3 h. Aftercooling to 0° C., water (100 mL) and aqueous NaOH (1 M, 5 mL) wascarefully added. The phases were separated and the aqueous phase wasextracted with ethyl acetate. After removal of the solvent, the compoundwas purified by flash chromatography (EtOAc/MeOH/TEA 80/15/5). Yield 0.3g (oil). ¹H-NMR (DMSO) 1.72 (q, 2H), 1.97 (d, 2H), 2.12 (t, 2H), 2.28(s, 3H), 2.45 (t, 2H), 2.77 (tt, 1H), 3.00 (d. 2H), 3.10-3.60 (m, 6H)3.72 (s, 2H), 6.25 (s, 2H), 7.14 (d. 1H), 7.35-7.45 (m, 4H), 7.55-7.65(m, 3H)

EXAMPLE 9

[0116]1-[2-[4-[5-aminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinon(9)

[0117]5-Cyano-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-1,2,3,6-tetrahydropyridin4-yl]-1H-indole (Perregaard, J.; Bges, K. P.; Hyttel,J.; Sánches, C.: J Med. Chem., 1992, 35, 1092-1101) (4.6 g) washydrogenated with PtO₂ in acetic acid at 3 ATO for 5 h. Ice and ammoniumhydroxide was added to pH 9 and the aqueous phase was extracted withethyl acetate. The combined organic phases were washed with water, driedover MgSO₄ and the solvent was removed in vacuo. The title compound waspurified by preparative HPLC (ethanol/NH₄OH 100/4). Yield 0.9 g, mp.171-175° C. (diethyl ether). ¹H-NMR (CDCl₃) 1.85 (d, 2H), 2.10 (d, 2H),2.25 (td, 2H), 2.60 (t, 2H), 2.90 (tt, 1H), 3.10 (d, 2H), 3.4 (q, 4H),3.6 (q, 2H), 3.95 (s, 2H), 4.70 (s, broad, 1H), 7.00 (s, 1H), 7.10-7.25(m, 3H), 7.30-7-50 (m, 3H), 7.60 (s, 1H). Analysis: Calc (corrected for1% water): C: 68.22, H: 7.01, N: 15.92 Found: C: 67.51, H: 6.90, N:15.37

Pharmacological Testing

[0118] As mentioned above, the compounds of the invention haveselectivity for cc,-adrenoceptors compared to related compounds such assertindole. The affinity of the compounds of the invention for tworeceptors, namely dopamine D₂ and the 5-HT₂A receptor, for which relatedcompounds such as sertindole have high affinity, has been determined.

[0119] The compounds of the invention have been tested using wellrecognised and reliable methods. The tests are as follows:

INHIBITION OF [³H]-PRAZOSIN BINDING TO α₁-ADRENOCEPTORS IN RAT BRAIN INVITRO

[0120] By this method, the inhibition by drugs of the binding of[³H-prazosin (0.25 nM) to α₁-andrenoceptors in membranes from rat brainis determined in vitro. Method and results in Hyttel & Larsen, J.Neurochem. 1985, 44, 1615-1622: Skarsfeldt & Hyttel, Eur. J. Phanmacol.1986,125, 323-340; Hyttel & Larsen, In: Research advances in NewPsychopharmacological Treatments for Alcoholism (eds. Naranjo &Sellers). Elsevier 1985, pp. 107-119.

Procedure

[0121] Male Wistar Mol:Wist) rats (125-250 g) are sacrificed and braintissue is dissected and weighed. The tissue is homogenized (UltraTurrax, 10 se) in 10 mL of ice cold 50 mM tris buffer pH 7.7 (at 25°C.). The homogenate is centiflged twice at 20,000 g for 10 min at 4° C.with rehomogenization of the pellet in 10 ml ice-cold buffer. The finalpellet is homogenized in 250 vol (w/v) ice-cold buffer.

[0122] Incubation tubes (96 deep-well titer plate) kept on ice receive50 mL of drug solution in water (or water for total binding) and 50 mLof [³H]-prazosin (final concentration 0.25 nM). The binding experimentis initiated by addition of 1000 mL of tissue suspension (final tissuecontent corresponds to 3 mg original tissue) and by placing the 96 deepwell titer plate in a 25° C. water bath. AU tests are made intriplicates. After incubation for 20 min, the samples are filtered on aBrandel harvester under vacuum (18 inch. Hg) through printed filtermat B(13 mm). Titerplates and filter are washed 1×10 sec flow 50 L/h with icecold buffer.

[0123] The filter mat is dried for 1 h at 110° C. and then placed in asample bag with Meltilex B/HS (14.5 g) and melted together on the T-Trayheat sealer. Radioactivity is determined by counting in the 1205Beta-plate scintillation counter (Wallac).

[0124] Specific binding is obtained by subtracting nonspecific bindingestimated in the presence of 1 mM of prazosin.

[0125] For determination of the inhibition of binding, fiveconcentrations of drugs covering 3 decades are used.

[0126] The ICs₅₀-value is determined as the concentration at which thebinding is 50% of the total binding in control samples minus thenonspecific binding in the presence of 1 mM of prazosin.

[0127] [³H]-prazosin from New England Nuclear (TRK 647; 0.37-1.1TBq/mmol).

INHIBITION OF [³H]-KETANSERIN BINDING TO SEROTONIN S₂ (5HT_(2A))RECEPTORS IN RAT CORTEX IN VITRO

[0128] By this method, the inhibition by drugs of the binding of[³H]-ketanserin (0.5 nM) to serotonin S₂ (5-HT₂) receptors in membranesfrom rat cortex is determined in vitro. Method in Hyttel, Pharmacology &Toxicology 1987, 61, 126-129.

Procedure

[0129] Male Wistar (Mol:Wist) rats (125-250 g) are sacrificed andcortical tissue is dissected and weighed. The tissue is homogenized(Ultra Turrax, 10 sec) in 10 mL of ice cold 50 mM tris buffer pH 7.7 (at25° C.). The centrifige glassware used in this step has been rinsed bysonication for 10 min in ethanol. The homogenate is centrifuged twice at20,000 g for 10 min. at 4° C., with rehomogenization of the pellet in 10mnL ice-cold buffer. The final pellet is homogenized in 250 vol (w/v)ice-cold buffer.

[0130] Incubation tubes (96 deep well titer plate) kept on ice receive50 mL of [³H]-ketanserin (final concentration 0.5 nM).

[0131] The binding experiment is initiated by addition of 1000 mL oftissue suspension (final tissue content corresponds to 4 mg originaltissue) and by placing the 96 deep well titer plate in a 37° C. waterbath. All tests are made in triplicates.

[0132] After incubation for 30 min, the samples are filtered on aBrandel harvester under vacuum (18 inch Hg) through printed filter mat B(13 mm). Titerplate and filter are washed 2×10 sec. flow 50L/h with icecold buffer.

[0133] The printed filter mat with purred labelled tissue are dried for1 h at 110 ° C. and hereafter placed in a sample bag with Meltilex B/HS14.5 g and melted together on the T-tray heat seal. Radioactivity isdetermined by counting in the 1205 beta-plate scintillation counter(Wallac).

[0134] Specific binding is obtained by subtracting the nonspecificbinding in the presence of 1 mM mianserin.

[0135] For determination of the inhibition of binding, fiveconcentrations of drugs covering 3 decades are used.

[0136] The IC₅₀-value is determined as the concentration at which thebinding is 50% of the total binding in control samples minus thenonspecific binding in the presence of 1 mM mianserin.

[0137] [³H]-ketanserin=(ethylene-³H)-ketanserin hydrochloride from NewEngland Nuclear, specific activity 60-80 Ci/nmnol.

Inhibition of [³H]-Spiperone Binding to Dopamnine D₂ Receptors in RatCorpus Striatum in vitro

[0138] By this method, the inhibition by drugs of the binding of[³H]-spiperone (=³H]-spiro-peridol) (0.5 nM) to dopamine D-2 receptorsin membranes from rat corpus striatum is determined in vitro. Method andresults in Hyttel, J. Acta. PharmacoL. ToxicoL. 1986, 59, 387. This is atest for dopamnine D₂ receptor binding affinity in vitro.

Procedure

[0139] Male Wistar (Mol:Wistar) rats (125-250 g) are sacrificed andstriatal tissue is dissected and weighed. The tissue is homogenized(Ultra Turrax, 10 sec.) in 10 mL of ice-cold 50 mM K-phosphate buffer pH7.4 (at 25° C.). The homogenate is centrifuiged twice at 20,000 g for 10min at 4° C. with rehomogenization of the pellet in 10 mL ice-oldbuffer. The final pellet is homogenized in 1300 vol (w/v) ice-coldbuffer.

[0140] Incubation tubes kept on ice in triplicate receive 100 μl of drugsolution in water (or water for total binding) and 4000 μl of tissuesuspension (final tissue content corresponds to 3.08 mg originaltissue). The binding experiment is initiated by addition of 100 μl of[³H]-spiperone (final concentration 0.5 nM) and by placing the tubes ina 37° C. water bath. After incubation for 10 min, the samples arefiltered under vacuum (0-50 mBar) through Whatman GF/F filters (25 mm).The tubes are rinsed with 5 mL ice-old buffer which are then poured onthe filters. Thereafter, the filters are washed with 2×5 mL of buffer.The filters are placed in counting vials and 4 mL of appropriatescintillation fluid (e.g. Picofluor™₁₅) are added. After shaking for 1 hand storage for 2 hrs in the dark, the content of radioactivity isdetermined by liquid scintillation counting. Specific binding isobtained by subtracting the nonspecific binding in the presence of 10 μMof 6,7-ADTN.

[0141] For determination of the inhibition of binding, fiveconcentrations of drugs covering 3 orders of magnitude are used.

[0142] The IC₅₀ value is determined as the concentration at which thebinding is 50% of the total binding in control samples minus thenonspecific binding in the presence of 10 μM of 6,7-ADTN

[0143] [³H]-Spiperone=[phenyl-4-³H]-spiperone from AmershamInternational plc. England, specific activity 15-25 Ci/mmol.

[0144] The results obtained are presented in table 1 below: TABLE 1IC₅₀values in nM Compound α₁ D₂ 5-HT_(2A) Sertindole 3.4 4.1 0.39Prazosin 0.36 11000 3300 7b 5.4 18 7c 50 7d 80 9  84

[0145] The IC₅₀ values for compounds of the present invention, a closelyrelated compound, sertindole, and a well known a,-antagonist, prazosin,are presented in Table 1. It is very clear that the compounds of theinvention have high affimty for α₁-adrenoceptors.

[0146] In particular, it is very clear that compared to the closelyrelated compound, sertindole, the compounds of the invention are highlyselective for the α₁-adrenoceptor.

Pharmaceutical compositions

[0147] The pharmaceutical compositions of this invention or those whichare manufactured in accordance with this invention may be administeredby any suitable route for example orally in the form of tablets,capsules, powders, syrups, etc., or parenterally in the form ofsolutions for injection. For preparing such compositions, methods wellknown in the art may be used, and any pharmaceutically acceptablecarriers, diluents, excipients, or other additives normally used in theart may be used.

[0148] Conveniently, the compounds of the invention are administered inunit dosage form containing said compounds in an amount of about 0.01 to100 mg.

[0149] The total daily dose is usually in the range of about 0.05-500mg, and most preferably about 0.1 to 50 mg of the active compound of theinvention.

Formulation Examples

[0150] The pharmaceutical formulations of the invention may be preparedby conventional methods in the art.

[0151] For example: Tablets may be prepared by mixing the activeingredient with ordinary adjuvants and/or diluents and subsequentlycompressing the mixture in a conventional tabletting machine. Examplesof adjuvants or diluents comprise: corn starch, potato starch, talcum,magnesium stearate, gelatine, lactose, gums, and the like. Any otheradjuvants or additives usually used for such purposes such ascolourings, flavourings, preservatives etc. may be used provided thatthey are compatible with the active ingredients. Solutions forinjections may be prepared by dissolving the active ingredient andpossible additives in a part of the solvent for injection, preferablysterile water, adjusting the solution to desired volume, sterilisationof the solution and filling in suitable ampules or vials. Any suitableadditive conventionally used in the art may be added, such as tonicityagents, preservatives, antioxidants, etc.

[0152] Typical examples of recipes for the formulation of the inventionare as follows:

[0153] 1) Tablets containing 5.0 mg of a compound of the inventioncalculated as the free base: Compound of the invention 5.0 mg Lactose 60mg Maize starch 30 mg Hydroxypropylcellulose 2.4 mg Microcrystallinecellulose 19.2 mg Croscarmellose Sodium Type A 2.4 mg Magnesium stearate0.84 mg

[0154] 2) Tablets containing 0.5 mg of a compound of the inventioncalculated as the free base: Compound of the invention 0.5 mg Lactose46.9 mg Maize starch 23.5 mg Povidone 1.8 mg Microcrystalline cellulose14.4 mg Croscarmellose Sodium Type A 1.8 mg Magnesium stearate 0.63 mg

[0155] 3) Syrup containing per millilitre: Compound of the invention 25mg Sorbitol 500 mg Hydroxypropylcellulose 15 mg Glycerol 50 mgMethyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005 ml Flavour 0.05mg Saccharin sodium 0.5 mg Water ad 1 mL

[0156]4) Solution for injection containing per millilitre: Compound ofthe invention 0.5 mg Sorbitol 5.1 mg Acetic Acid 0.05 mg Saccharinsodium 0.5 mg Water ad 1 mL

What is claimed is:
 1. A 5-aminoalkyl and 5-aminocarbonyl substitutedindole derivative having the general formula

wherein R¹ is —(CH₂)_(n-1)-CONR¹⁰R¹¹ , —(CH₂)_(n)-NR¹⁰R¹¹ or

wherein R¹⁰ and R¹¹ are independently selected from hydrogen,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, aryl-C₁₋₆-alkyl, aryl, acyl,amino-C₁₋₆-alkyl and mono- or di-C₁₋₆-alkylamino-C₁₋₆-alkyl, R¹² ishydrogen, or C₁₋₆-alkyl, n is 1 to 3 and q is 2 to 5; G is N, C, or CH;the dotted line meaning a bond when G is C, and the dotted line meaningno bond when G is CH, or N; Ar is phenyl optionally substituted with oneor more substituents independently selected from halogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, hydroxy, trifluoromethyl and cyano, or Ar is 2-thienyl,3-thienyl, 2-furanyl, 3-furanyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl,2-pyridyl, 3-pyridyl, or 4-pyridyl; R², R³, R⁴ and R⁵ are independentlyselected from hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, hydroxy, halogentrifluoromethyl, nitro, cyano, amino, C₁₋₆-alkylamino andC₁₋₆-dialkylamino; R⁶ is hydrogen, or C₃₋₈-cycloalkyl,C₃₋₈-cycloalkyl-C₁₋₆-alkyl, C₂₋₆-alkyl, which may optionally besubstituted with one or two hydroxy groups, any hydroxy group presentbeing optionally esterified with an aliphatic carboxylic acid havingfrom two to twenty-four carbon atoms inclusive, or R⁶ is a group of theFormula II or III:

wherein m is an integer from 2-6; W is O or S; U is N or CH; Z is—(CH₂)_(p), p being 2 or 3, or Z is —CH═CH— or 1,2-phenylene optionallysubstituted with halogen or trifluoromethyl, or Z is —COCH₂- or —CSCH₂-;V is O, S, CH₂, or NR⁹, wherein R⁹ is hydrogen, or C₁₋₆-alkyl,C₂₋₆-alkenyl or C₂₋₆-alkenyl, which may optionally be substituted withone or two hydroxy groups, or a C₃₋₈-cycloalkyl orC₃₋₈-cycloalkyl-C₁₋₆-alkyl group; X is N, C, or CH; Y is N, C, or CH;provided at least one of X and Y is N; and R⁷ is hydrogen, orC₁₋₆-alkyl; or a pharmaceutically acceptable acid addition salt thereof.2. A compound according to claim 1, wherein R¹ is —CONR¹⁰R¹¹ or—(CH₂)_(n),-NR¹⁰R¹¹ wherein R¹⁰ and R¹¹ are independently selected fromhydrogen and C₁₋₆ alkyl.
 3. A compound according to claim 1, wherein R⁶is a group of formula II..
 4. A compound according to claim 1, which isselected from1-(4-Fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidinyl]-N-methyl-1H-indole-5-carboxamide;NN-Dimethyl-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidinyl]-1H-indole-5-carboxamide;1-[2-[4-[5-Dimethylaminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinon;1-2-[4-[5-Dimethylaminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-2-imidazolidinon;1-[2-[4-[1-(4-fluorophenyl)-5-methylaminomethyl-1H-indol-3-yl]-1piperidinyl-piperidinyl]ethyl-2-imidazolidinon; or1-[2-[4-[5-aminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2--imidazolidinon;or a pharmaceutically acceptable acid addition salt thereof.
 5. Acompound according to claims 1 to 4 which is radio-labeled.
 6. Acompound according to claim 5 which is radiolabeled with [¹¹C]-methyl.7. A pharmaceutical composition comprising at least one compoundaccording to claim 1 or a pharmaceutically acceptable acid addition saltthereof, and optionally a second pharmaceutically active ingredient incombination with one or more pharmaceutically acceptable carriers ordiluents.
 8. A method for the treatment of a disorder or diseaseresponsive to antagonism of α₁-adrenoceptors in a mammal comprisingadministering a compound according to claim 1 or an acid addition saltthereof and optionally a second pharmaceutically active ingredient tosaid mammal.
 9. A method for the treatment of psychosis in a mammalcomprising administering a compound according to claim 1 or an acidaddition salt thereof and optionally a second agent having antipsychoticactivity to said mammal.